Advances in the field of biotechnology have given rise to significant advances in the treatment of previously-intractable diseases such as cancer, genetic diseases, arthritis and AIDS. Many such advances involve the administration of oligonucleotides and other nucleic acids to a subject, particularly a human subject.
Oligonucleotides have been administered by various routes. For example, oligonucleotides administered by parenteral routes have been shown to be effective for the treatment of diseases and/or disorders. See, e.g., U.S. Pat. No. 5,595,978, Jan. 21, 1997 to Draper et al., which discloses intravitreal injection as a means for the direct delivery of antisense oligonucleotides to the vitreous humor of the mammalian eye. See also, Robertson, Nature Biotechnology, 1997, 15:209 and Anon., Genetic Engineering News, 1997, 15:1, each of which discuss the treatment of Crohn's disease via intravenous infusions of antisense oligonucleotides.
The administration of oligonucleotides via the lung for the treatment of pulmonary disorders is attractive because oligonucleotide is delivered directly to the target organ. For reviews see, for example, Nyce, J. W., Exp. Opin. Invest. Drugs (1997) 6(9):1149-1156; Schreier, H., Advanced Drug Delivery Reviews, 19, (1996) 1-2; Wu-Pong, S., and Byron, P. R., Advanced Drug Delivery Reviews, 19, (1996) 47-71; and Phan, S. H., Thorax 1995; 50: 415-421. However, most reports have focused upon intratracheal rather than inhalation delivery of large nucleic acids that are antisense constructs rather than of antisense oligonucleotides having smaller molecular weights. See, for example, Georges, R. N., et al., Cancer Research 53, 1743-1746 (1993) (prevention of orthotopic human lung cancer growth by intratracheal installation of a retroviral antisense K-ras construct); and Yoshimura, K., et al., Nucleic Acids Research, Vol. 20, No. 12, 3233-3240 (1992) (expression of the human cystic fibrosis transmembrane conductance regulator gene in the mouse lung after in vivo intratracheal plasmid-mediated gene transfer).
Antisense oligonucleotides have been shown to demonstrate antisense effect upon cells of various diseases or disorders, including cancer. See, for example, Dosaka-Akita et al., Cancer Res. 55, 1559-1564 (1995) (inhibition of proliferation by L-myc antisense DNA for the transitional initiation site in human small cell lung cancer).
There is a long-felt need for compositions which can effectively provide for the pulmonary delivery of nucleic acids, particularly oligonucleotides, more particularly oligonucleotides having one or more chemical modifications, together with methods for using such compositions to deliver such oligonucleotides and nucleic acids into the lung of an animal. The present invention is directed to these, as well as other, important ends.